Type 1 diabetes (T1D) is an autoimmune disease resulting from the interaction of genetic and environmental factors. The reasons auto reactive T cells become activated and mediate destruction of insulin-producing beta cells are not fully understood, but insights can be gained from one of the best animal models for T1D, the nonobese diabetic (NOD) mouse. NOD mice develop T1D spontaneously and share conserved immunological and physiological disease processes with humans affected by T1D. In both humans and NOD mice, several loci, including the major histocompatibility complex, are also important in the disease process. However, human genetic studies have had limited success for identifying the genes at these loci. An alternative approach which avoids the complexity of human studies is identification of susceptibility alleles within the NOD mouse, where controlled mating can be used to precisely map and characterize a disease gene. We have established NOD mouse strains which contain different chromosomal intervals derived from a non-diabetic mouse strain and confirmed the location of two different susceptibility loci, termed Idd11 and Idd14, on chromosome 4 and 13 respectively. These mouse chromosomes are syntenic with human chromosomal regions that have been linked to T1D. The major goal of this project is to characterize T1D susceptibility genes which may play a role in the genetics of both human and mouse disease progression. The main approach will involve the genetic and immunological characterization of Idd11 and Idd14 using the NOD mouse strain. The questions to be investigated are: 1) What are the smallest definable chromosomal regions that contain Idd11 and Idd14? 2) What role in the disease process does Idd11 and Idd14 play? 3) Which actual genes are Idd11 and Idd14? A number of different gene discovery strategies will be used including: congenic mouse strains, BAG transgenic complementation; immunohistochemical staining of relevant tissues, flow cytometric analysis of relevant cell types, cytokine assays, genetic and expression profiling, and allelic substitution using mouse embryonic stem cells. By defining these susceptibility genes it should become possible to better understand the molecular events underlying predisposition to T1D, as well as identify biochemical pathways which may offer therapeutic targets for disease prevention.